Design, synthesis, and pharmacological evaluation of N-bicyclo-5-chloro-1H-indole-2-carboxamide derivatives as potent glycogen phosphorylase inhibitors.
As a result of the various N-bicyclo-5-chloro-1H-indole-2-carboxamide derivatives with a hydroxy moiety synthesized in an effort to discover novel glycogen phosphorylase (GP) inhibitors, 5-chloro-N-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-indole-2-carboxamide (5b) was found to have potent inhibitory activity. The introduction of fluorine atoms both at a position adjacent to the hydroxy group and in the central benzene moiety lead to the optically active derivative 5-chloro-N-[(5R)-1,3,6,6-tetrafluoro-5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1H-indole-2-carboxamide (25e(alpha), which was the most potent compound in this series (IC(50)=0.020microM). This compound inhibited glucagon-induced glucose output in cultured primary hepatocytes with an IC(50) value of 0.69microM, and showed oral hypoglycemic activity in diabetic db/db mice at 10mg/kg. Compound 25e(alpha) also had an excellent pharmacokinetic profile, with high oral bioavailability and a long plasma half-life, in male SD rats. The binding mode of 25e(alpha) to this molecule and the role of fluorine atoms in that binding were speculated in an enzyme docking study.
Onda
Kenichi
K
Drug Discovery Research, Astellas Pharma Inc., 5-2-3 Toukoudai, Tsukuba, Ibaraki 300-2698, Japan.
Shiraki
Ryota
R
Ogiyama
Takashi
T
Yokoyama
Kazuhiro
K
Momose
Kazuhiro
K
Katayama
Naoko
N
Orita
Masaya
M
Yamaguchi
Tomohiko
T
Furutani
Masako
M
Hamada
Noritaka
N
Takeuchi
Makoto
M
Okada
Minoru
M
Ohta
Mitsuaki
M
Tsukamoto
Shin-ichi
S
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005947:Glucose; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors*; D022781:Hepatocytes / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008820:Mice, Obese; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
C534078:5-chloro-N-((5R)-1,3,6,6-tetrafluoro-5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-indole-2-carboxamide; C534077:5-chloro-N-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-indole-2-carboxamide; D001549:Benzamides; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007211:Indoles; D024981:Glycogen Phosphorylase; D005947:Glucose